Acute Myelocytic Leukemia (AML)

Acute myelocytic leukemia is a myeloproliferative disorder characterized by the accumulation of abnormal myeloid precursors in the bone marrow. The disease may be associated with end organ dysfunction resulting from an infiltration with leukemic cells, but mortality is most commonly due to the consequences of bone marrow failure.

Acute Myelocytic Leukemia originates from the following process: neoplastic.

Of note, leukocytosis is not uncommon in AML patients. In the case of hyperleukocytosis (>100 x 109/l), symptoms of leukostasis may manifest. Such symptoms comprise ocular and cerebrovascular hemorrhages and dysfunction [10].

Jaw & Teeth

Symptoms can include: pale skin tiredness breathlessness frequent infections unusual and frequent bleeding, such as bleedinggums or nosebleeds In more advanced cases, AML can make you extremely vulnerable to life-threatening infections or serious internal[nhs.uk]

Liver, Gall & Pancreas

The major clinical manifestations of malaise, hepatosplenomegaly, anemia, and leukocytosis are related to abnormal, excessive, unrestrained overgrowth of granulocytes in the bone marrow.[medical-dictionary.thefreedictionary.com]

He had no hepatosplenomegaly or lymph node enlargement but his hemogram showed pancytopenia, with 8.2 g/dL of hemoglobin, a hematocrit of 25.3% and a white blood cell count of 2 x 10 9 /µL (8% neutrophils, 41% lymphocytes and 46% blast cells).[scielo.br]

Side effects may include: Hair loss Nausea Mouth sores Fatigue Increased risk of infection In the second treatment phase, steps are taken to kill any remaining leukemia cells that could cause a relapse.[drugs.com]

The early signs of AML may be similar to the flu or other common diseases with fever , weakness and fatigue , loss of weight and appetite, and aches and pains in the bones or joints.[medicinenet.com]

Patients generally present with fever, which may occur with or without specific documentation of an infection.[emedicine.medscape.com]

Symptoms of AML include: Fever Shortness of breath Easy bruising or bleeding Bleeding under the skin Weakness or feeling tired Weight loss or loss of appetite Tests that examine the blood and bone marrow diagnose AML.[nlm.nih.gov]

Although infections can be of any type, typical symptoms include: Fever Runny nose Cough Chest pain or shortness of breath Pain with urinating Diarrhea, occasionally Infections of the bloodstream, called sepsis, and pneumonia are the most dangerous Reviewed[ucsfhealth.org]

Symptoms of AML may include any of the following: Bleeding from the nose Bleeding and swelling (rare) in the gums Bruising Bone pain or tenderness Fever and fatigue Heavy menstrual periods Pale skin Shortness of breath (gets worse with exercise) Skin[pennstatehershey.adam.com]

The major clinical manifestations of malaise, hepatosplenomegaly, anemia, and leukocytosis are related to abnormal, excessive, unrestrained overgrowth of granulocytes in the bone marrow.[medical-dictionary.thefreedictionary.com]

Although infections can be of any type, typical symptoms include: Fever Runny nose Cough Chest pain or shortness of breath Pain with urinating Diarrhea, occasionally Infections of the bloodstream, called sepsis, and pneumonia are the most dangerous Reviewed[ucsfhealth.org]

The main clinical picture consists of a short time period with pallor, fatigue, fever, infections and hemorrhages.[orpha.net]

Symptoms Symptoms can include : a high fever a large number of infections over a short period breathlessness fatigue and confusion hyperhidrosis (sweating a lot) pain in the joints, and perhaps also the bones pallor skin bruising easily slurred speech[medicalnewstoday.com]

Symptoms include fatigue, pallor, easy bruising and bleeding, fever, and infection; symptoms of extramedullary leukemic infiltration are present in only about 5% of patients (often as skin manifestations).[merckmanuals.com]

A blood count will show thrombocytopenia, a decreased number of platelets. recurrentinfections – Although there may be an unusually high number of white blood cells on your child’s blood count, these white blood cells are immature and do not fight infection[danafarberbostonchildrens.org]

In occasional cases symptoms like lymphadenopathy, enlarged tonsils, shifting lameness in legs, ocular tumors and recurrentinfections are also seen.[wearethecure.org]

The risk of the disease is increased among people who have been exposed to massive doses of radiation and who have certain blood dyscrasias, such as polycythemia, primary thrombocytopenia, and refractoryanemia.[medical-dictionary.thefreedictionary.com]

These include: anaemia due to a lack of red cells; causing persistent tiredness, dizziness, paleness, or shortness of breath when physically active; frequent or repeated infections and slow healing, due to a lack of normal white cells, especially neutrophils[leukaemia.org.au]

The symptoms of the anemia may include fatigue, dizziness, headache, paleness of the skin, or, infrequently, congestive heart failure.[encyclopedia.com]

The symptoms of the anemia may include fatigue, dizziness, headache, paleness of the skin, or, infrequently, congestive heart failure.[encyclopedia.com]

This can cause symptoms for the patient, including headache, shortness of breath and pain.[oncolink.org]

Acute leukemia is characterized by fatigue, headache, sore throat, and dyspnea, followed by symptoms of acute tonsillitis, stomatitis, bleeding from the mucous membranes of the mouth, alimentary canal, and rectum, and pain in the bones and joints.[medical-dictionary.thefreedictionary.com]

Skin

However, the symptoms of all types of leukemia are generally the same and include: fatigue (tiredness) and weakness swollen lymph nodes infections (like bronchitis or tonsillitis ) that keep coming back fever nightsweats easy bruising or petechiae (tiny[kidshealth.org]

They include black-and-blue marks or bruises occurring for no reason or because of a minor injury, the appearance of pin-head sized spots under the skin, called petechiae, or prolonged bleeding from minor cuts.[diagnose-me.com]

However, the symptoms of all types of leukemia are generally the same and include: fatigue (tiredness) and weakness swollen lymph nodes infections (like bronchitis or tonsillitis ) that keep coming back fever night sweats easy bruising or petechiae (tiny[kidshealth.org]

These signs and symptoms include: Infections due to lack of neutrophils Increased bleeding secondary to platelet deficiency Bleeding due to minor trauma, bleeding of the gums, mid-cycle menstrual bleeding, or heavy bleeding with menstruation Petechiae[physio-pedia.com]

Myeloproliferative diseases can also be accompanied by occasional vomiting, diarrhea, dyspnea (shortness of breath) and other neurological deficits including disorientation, ataxia (lack of muscle coordination) and seizures.[wearethecure.org]

The deficient production of red blood cells can lead to patient complaints of weakness, fatigue, or dyspnea on exertion.[clevelandclinicmeded.com]

gastrointestinal

Although infections can be of any type, typical symptoms include: Fever Runny nose Cough Chest pain or shortness of breath Pain with urinating Diarrhea, occasionally Infections of the bloodstream, called sepsis, and pneumonia are the most dangerous Reviewed[ucsfhealth.org]

They can include: hair loss nausea diarrhea severe infections With intensive chemotherapy, admitting the patient to the hospital for around a week can help manage the side effects.[medicalnewstoday.com]

At the completion of induction I chemotherapy, patients were discharged regardless of the neutrophil counts or platelet counts if patients appeared clinically stable and well without fever and had no severe nausea/vomiting, diarrhea, abdominal pain, or[hindawi.com]

Myeloproliferative diseases can also be accompanied by occasional vomiting, diarrhea, dyspnea (shortness of breath) and other neurological deficits including disorientation, ataxia (lack of muscle coordination) and seizures.[wearethecure.org]

A doctor should be consulted if any of the following problems occur: Fever Shortness of breath Easy bruising or bleeding Petechiae (flat, pinpoint spots under the skin caused by bleeding) Weakness or feeling tired Weight loss or loss of appetite Tests[my.clevelandclinic.org]

BonePain or Tenderness Gum Swelling : This symptom is rare Acute Myeloid Leukemia Diagnosis If symptoms for acute myeloid leukemia persist, a doctor may recommend several tests: Physical Exam : A swollen liver, spleen or lymph nodes may be indicative[knowcancer.com]

Symptoms of AML may include any of the following: Bleeding from the nose Bleeding and swelling (rare) in the gums Bruising Bonepain or tenderness Fever and fatigue Heavy menstrual periods Pale skin Shortness of breath (gets worse with exercise) Skin[pennstatehershey.adam.com]

cardiovascular

Other symptoms of anemia include dyspnea upon exertion, dizziness, and, in patients with coronary artery disease, anginal chestpain.[emedicine.medscape.com]

Although infections can be of any type, typical symptoms include: Fever Runny nose Cough Chestpain or shortness of breath Pain with urinating Diarrhea, occasionally Infections of the bloodstream, called sepsis, and pneumonia are the most dangerous Reviewed[ucsfhealth.org]

Other symptoms may include bone pain, swollen lymph nodes, swollen gums, chestpain and abdominal discomfort due to a swollen spleen or liver.[leukaemia.org.au]

urogenital

Ears

Workup

Laboratory analyses of blood samples including a complete cell count with differential count are generally the first step towards the diagnosis of AML. Indeed, the incidental detection of hematological anomalies that precede the onset of clinical symptoms is not uncommon in older patients undergoing routine screenings and may allow for an early diagnosis of leukemia and a timely initiation of treatment. Pancytopenia or any combination of anemia, granulocytopenia, and thrombocytopenia are often observed and may indicate imminent or existing bone marrow failure. As has been mentioned above, leukocytosis and even hyperleukocytosis may also be observed.

Subsequently, an aspiration of bone marrow needs to be performed. Immunohistochemical staining for myeloperoxidase expression or immunophenotyping of bone marrow blasts should be performed to confirm the involvement of the myeloid lineage. In general, the presence of more than 20% leukemic blasts in bone marrow specimens is required for the diagnosis of AML [11]. Furthermore, samples should be analyzed regarding their cytogenetic and molecular features. A detailed characterization of blasts is necessary for prognostic and therapeutic reasons.

In order to prevent and identify possible complications of AML, a comprehensive metabolic profile, as well as coagulation studies, should be ordered. Diagnostic imaging may be indicated to assess the condition of the patient's heart, lungs and possible central nervous system involvement.

Laboratory

Serum

Urine

Cerebrospinal Fluid

Imaging

X-ray

Treatment

Cytotoxic chemotherapy and hematopoietic stem cell transplantation are the mainstays of therapy. Distinct chemotherapeutic regimens have been used in AML patients, but the standard induction therapy consists of anthracyclines (e.g., daunorubicin at a minimum dose of 60 mg/m², idarubicin at a dose of approximately 10 mg/m², for three days) and cytarabine (at a dose of up to 200 mg/m², for seven days) [11]. Such treatment should be initiated as soon as possible and leads to complete remission in the majority of adults aged less than 60 years. Older patients known to have adverse cytogenetics may be considered for alternative approaches, e.g., investigational regimens or mild cytoreductive therapy.

Post-remission strategies include intense chemotherapy with high-dose cytarabine, prolonged maintenance treatment, as well as autologous and allogeneic stem cell transplantation. Precise recommendations depend on prior risk assessment and genetic features displayed by clonal tumor cells. For instance, allogeneic stem cell transplantation is associated with the lowest rates of recurrence, but also with high treatment-related mortality. Thus, it is typically considered for high-risk AML patients if a matched donor is available.

Patients presenting with bone marrow failure should be stabilized before further therapeutic measures are undertaken. Here, medical care may include the transfusion of blood products, antimicrobial therapy, and leukapheresis, as needed. AML treatment may be restricted to palliative measures in patients suffering from severe comorbidities.

It is beyond the scope of this article to discuss target-oriented therapy for individual types of AML, but excellent reviews on this topic are available elsewhere [12].

Prognosis

AML is generally associated with an unfavorable prognosis; if left untreated, it is uniformly fatal. Despite the provision of optimum medical care, most patients die from bone marrow failure. Five years after diagnosis, only 21% of AML patients remain alive, but this value is highly age-dependent: More than half of AML patients aged less than 45 years survive for more than five years, in contrast to less than 10% of those aged 65 years and older [7].

It is important to note that median survival times observed in patients diagnosed with distinct subtypes of AML vary largely [8]:

Translocations t(8;21)(q22;q22), t(15;17)(q24;q21), and inv(16)(p13;q22) are associated with a favorable prognosis and a 5-year-survival rate of 55%.

Patients with AML and normal cytogenetics constitute the largest subgroup and are usually assigned an intermediate prognosis; their 5-year-survival rates range between 24 and 42%. Here, the identification of genetic abnormalities of malignant cells may allow for a more reliable prognosis. The interested reader is referred to an extensive review on this topic [9].

Monosomy 5 or 7, 11q23 rearrangements and complex chromosomal aberrations are related to a poor prognosis; the respective 5-year-survival rate is only 11%.

Good responses are observed after treatment with retinoids, which are drugs chemically related to vitamin A. myelomonocytic leukemia (M4 or M4 variant with eosinophilia [M4E] )—The bone marrow and circulating blood have variable amounts of differentiated[healthcommunities.com]

Whilst the majority of inv(16)(p13q22) have been identified as AML M4EO, this abnormality may occasionally been seen in other myeloid malignancies, including AML M2, M4 without eosinophilia, M5 and MDS.[atlasgeneticsoncology.org]

Gingivitis due to neutropenia can cause swollen gums, and thrombocytopenia can cause the gums to bleed.[emedicine.medscape.com]

Low numbers of platelets can lead to petechiae, gingival bleeding, ecchymosis, epistaxis, or menorrhagia.[clevelandclinicmeded.com]

Acute monocytic leukemia comprises 3% to 6% of cases and is more common in adults.[ 63 ] Common clinical features for both acute leukemias include bleeding disorders, extramedullary masses, cutaneous and gingival infiltration, and central nervous system[dana-farber.org]

Diagnostic methods Diagnosis relies on laboratory findings showing anemia, thrombocytopenia and leucopenia or leukocytosis which result from disturbed hematopoietic function due to bone marrow and peripheral blood infiltration by immature blast cells.[orpha.net]

Complications & Concerns of Leukemia and Treatment Leukocytosis Some people with AML will present with a very high white blood cell count, which is called leukocytosis.[oncolink.org]

The major clinical manifestations of malaise, hepatosplenomegaly, anemia, and leukocytosis are related to abnormal, excessive, unrestrained overgrowth of granulocytes in the bone marrow.[medical-dictionary.thefreedictionary.com]

However, CML should be distinguished from severe neutrophilic leukocytosis’ (condition in which all white blood cells are affected) or ‘leukemoid reactions’ (elevated white blood cell count that is a physiologic reaction to stress or infection) which[wearethecure.org]

Acute leukemia is characterized by fatigue, headache, sore throat, and dyspnea, followed by symptoms of acute tonsillitis, stomatitis, bleeding from the mucous membranes of the mouth, alimentary canal, and rectum, and pain in the bones and joints.[medical-dictionary.thefreedictionary.com]

Etiology

AML is the result of anomalies in hematopoietic cell differentiation and proliferation. These are essentially due to chromosomal aberrations that are discussed in detail below. Both endogenous and exogenous factors may contribute to the malignant transformation of myeloid precursors. In this context, the following risk factors have been identified [2]:

Epidemiology

AML is the most common acute leukemia in adults, and about 20,000 cases are diagnosed each year in the United States alone [3]. The latter corresponds to an annual incidence of about 1 in 15,000 inhabitants, and similarly, high incidence rates have only been reported in Europe and Australia [4]. Age-specific incidence rates follow a bimodal distribution: Infants and young children are more likely to develop AML than older children and young adults, while highest incidence rates are observed in the elderly population. Accordingly, the patients' median age at symptom onset is 65 years. People age 65 years and older have a tenfold increased risk of developing AML when compared with young adults [2]. Moreover, incidence rates depend on race and gender. For instance, Caucasians are more prone to develop AML at very young ages compared to patients of African descent, while the disease is more frequently diagnosed in older black children and adolescents. Males are affected slightly more often than females.

Sex distribution

Age distribution

Pathophysiology

Only a minor proportion of cases can unequivocally be related to either of the above -mentioned risk factors. Indeed, AML is most likely not the result of a single event or gene defect, but the consequence of a susceptible myeloid precursor being subjected to additional influences that induce leukemogenesis. According to the so-called "2-hit-hypothesis", a first mutation confers a proliferative and survival advantage to the respective cell. Only subsequent rearrangements provoke the onset of leukemia: They result in a maturation arrest and reduced apoptosis [5]. The molecular mechanisms underlying this development vary depending on the precise chromosomal aberration(s) and environmental factor(s). The heterogeneity of leukemogenesis is best illustrated by the diversity of acquired cytogenetic anomalies that may be detected in bone marrow specimens obtained from AML patients:

As the presence of genetic features is of prognostic and therapeutic relevance, the identification of recurrent genetic abnormalities constitutes the basis of modern AML classification [6]. Furthermore, AML may be related to Down syndrome, myelodysplasia or prior chemotherapy. It is important to note that the current World Health Organization classification of myeloid neoplasms and acute leukemia additionally lists AML, not otherwise specified, as a subtype of AML.

Prevention

According to the information given above, avoidance of risk factors may be of help to prevent AML. Corresponding measures may include refraining from tobacco consumption and reducing the exposure to radiation and chemical carcinogens, inter alia by implementing occupational safety standards.

Summary

The term acute myelocytic leukemia (AML), possibly also referred to as acute myeloid leukemia or acute myelogenous leukemia, describes a group of myeloproliferative disorders. In all types of AML, malignant transformation of myeloid precursor cells is associated with a maturation arrest and impaired apoptosis. This may affect precursors of granulocytes, monocytes, mast cells, erythrocytes or platelets. With regards to the prevailing stage of degenerated blasts, the following subtypes of AML may be distinguished (French-American-British classification, [1]):

In any case, the clonal population of tumor cells interferes with bone marrow function and hematopoiesis. Affected individuals thus tend to develop pancytopenia and present with symptoms consistent with anemia, immunodeficiency and a propensity to bleed. To date, treatment of AML mainly consists of non-specific measures like cytotoxic chemotherapy and hematopoietic stem cell transplantation. Unfortunately, this approach continues to be related to poor survival rates.

Recent studies shed more light on the molecular mechanisms underlying leukemogenesis in single types of AML and emphasize the need for a personalized, target-oriented therapy. Treatment recommendations are thus to be expected to change in the near future.

Patient Information

Acute myelocytic leukemia (AML), sometimes also referred to as acute myeloid leukemia, is a myeloproliferative disorder and hematological malignancy. It is characterized by an excess proliferation of myeloid precursors in the bone marrow. These cells originate from hematopoietic stem cells and are supposed to differentiate into red blood cells, white blood cells and platelets. Because the development of these cell populations involves distinct intermediate stages, patients may suffer from different subtypes of AML. Acute promyelocytic leukemia, for instance, is defined as an accumulation of abnormal promyelocytes, which are granulocyte precursors. In any case, the presence of abundant tumor cells in the bone marrow interferes with this organ's function and hematopoiesis. Eventually, this condition may lead to bone marrow failure. Symptoms of imminent bone marrow failure may be anemia, recurrent infections with opportunistic pathogens and a propensity to bleed.

Although several endogenous and exogenous factors have been related to the onset of AML, the etiology of this type of blood cancer remains poorly understood. Few cases are related to Down syndrome, Klinefelter syndrome, myelodysplasia, prior cytotoxic chemotherapy, as well as exposure to chemical carcinogens and radiation, but in the majority of patients, causes cannot be identified. In order to diagnose AML, bone marrow specimens have to be analyzed. A detailed characterization of tumor cells is necessary for prognostic and therapeutic reasons. To date, treatment primarily consists of cytotoxic chemotherapy and hematopoietic stem cell transplantation, but more specific approaches may be feasible in certain types of AML. To summarize, an individual patient's prognosis depends on the type of AML, on the genetic features displayed by degenerated myeloid precursors, on the patient's age and overall condition, and the involvement of extramedullary sites.

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